1. The Field of the Invention
The subject matter of the present invention comprises the use of estradiol valerate or estradiol in combination with 17α-cyanomethyl-17β-hydroxyestra-4, 9-dien-3-one (dienogest) to make a multiphase combination preparation for oral therapy of dysfunctional uterine bleeding and for oral contraception. This multiphase combination preparation contains a first phase of 2 daily dosage units, each consisting of 3 mg of estradiol valerate or less than 3 mg of estradiol; a second phase of two groups of daily dosage units, a first group of which consists of 5 daily dosage units, each consisting of a combination of 2 mg of dienogest with 2 mg of estradiol valerate or with less than 2mg of estradiol, and a second group of which consists of 17 daily dosage units, each consisting of a combination of 3 mg of dienogest with 2 mg of estradiol valerate or with less than 2 mg of estradiol; a third phase of 2 daily dosage units, each consisting of 1 mg of estradiol valerate or of less than 1 mg estradiol; and another phase of 2 daily dosage units of pharmaceutically harmless placebo, which contains a total number of 28 daily dosage units. The total number of daily dosage units of the multiphase combination preparation is sufficient for 28 days.
2. Description of the Related Art
Dysfunctional uterine bleeding (DUB) is a frequent clinical problem in gynecology and affects up to 33% of women presenting themselves for gynecological medical examinations on an outpatient basis (Awward J. T., Toth T. L., Schiff I., Abnormal Uterine Bleeding in the Perimenopause, Int. J. Fertil. 1993; 38, pp. 261-9). The symptoms of DUB are:                extended menstrual bleeding (>7 days)        frequent bleeding (interval between bleeding episodes of less than or equal to 21 days)        increased bleeding (more than or equal to 80 ml).        
DUB requires a diagnosis by exclusion, namely organic causes such as myoma, polyps or cancer must be excluded before a DUB diagnosis can be made.
DUB is associated with anovulation as well as ovulation. Such bleeding disturbances are due to an imbalance between the estrogen-stimulating build-up phase (proliferation) of the endometrium and the gestagenic transformation of the endometrium. If the DUB symptoms are a result of chronic anovulation, the endometrium is often exposed to increased gestagenic proliferation. Such proliferation can lead to hyperplasia of the endometrium besides the bleeding disturbances (Speroff, et al., Clinical Gynecologic Endocrinology and Infertility, sixth edition, Lippincott, Williams and Wilkins, 1999).
Hyperplasia of the endometrium is a risk factor for the onset of endometrial cancer.
Fraser, I. S., Aust. N Z J. Obstet. Gynaecol. (1990) 30 (4), pp. 353-356, reported the treatment of dysfunctional uterine bleeding by administration of 5 mg of norethisterone, three times daily, or 10 mg of medroxyprogesterone acetate, three times daily, as the only high-dosage gestagen, in each case for 14 days from the 12th to the 25th day of the cycle in 6 anovulatory women and for 20 days from the 5th, to the 25th day of the cycle in ten ovulatory women. In both groups, the duration of the bleeding period was reduced. Reliable contraception was not attained.
Hickey M., Higham J. and Fraser I S, The Chochrane Library, Issue 3 2004 (Mickey M, Higham J, Fraser I S, Progestogens Versus Estrogens and Progestogens for Irregular Uterine Bleeding Associated with Anovulation (Cochrane Review), In The Cochrane Library, Issue 3 2004, Chichester, UK: John Wiley & Sons, Ltd) describe in a review article the low tolerance of women for irregular and extensive bleeding. They describe the rationale behind the use of gestagens to achieve a transformation of the endometrium and thus to create more stable menstruation cycles. The conclusion of the article is that clinical data from randomized studies demonstrating the efficacy of the described treatments are currently not available.
Steiner, R., Schweiz. Rundsch. Med. Prax. (2000) 91 (46), pp. 1967-1974, also points out that dysfunctional uterine bleeding should be treated with, among other methods, high-dosage gestagens, estrogens or a combination of both.
Steiner sees a treatment regimen in the oral administration of 0.01 mg of ethinyl estradiol with 2 mg of norethisterone acetate for 8 days in decreasing dosages, namely 6, 5, 4, 3, 3, 3, 3, 3/day. Besides the hormonal approach, Steiner postulates the possibility of treating an acute bleeding situation with tranexaminic acid, up to 4×2 tablets per day.
Davis, A., Obstet. Gynecol. (2000) 96 (6), pp. 913-920, describes the treatment of dysfunctional uterine bleedings by a three-step administration of ethinyl estradiol (EE)/norgestimate (NGM) followed by hormone-free administration of placebo for three 28-day cycles. According to the treatment regimen, the EE dosage remains constant over 21 days (0.035 mg of EE), the NGM dose increases over 21 days (7 daily dosage units of 0.180 mg of NMG and 7 daily dosage units of 0.215 mg of NMG and 7 daily dosage units of 0.250 mg of NMG), followed by a 7-day hormone-free placebo administration. The placebo-controlled study carried out by Davis included 45% of women with increased menstrual bleeding (metrorrhagia, menometrorrhagia and polymenorrhea) and about 55% of women with reduced menstrual bleeding (oligomenorrhea). The highest degree of success compared to placebo was achieved in women with reduced menstrual bleeding in whom regular withdrawal bleeding was induced. Oligomenorrhea is not necessarily a component of the DUB symptom group and is not recognized as an ailment worthy of treatment.
U.S. Pat. No. 6,782,282 discloses that generally extended use (3 months) of oral contraceptives can be used for the treatment of menorrhagia—a form of dysfunctional uterine bleeding.